Ypsilon,ypsilon-diaryl-alpha,beta-dihalocrotonic acids

ABSTRACT

NOVEL THERAPEUTIC COMPOUNDS OF THE Y,Y&#39;&#39;-DIARYL-A,B-DIHALOCROTONIC ACID TYPE SPECIFICALLY THE DICHLORO AND DIBROMO COMPOUNDS AND PROCESSES FOR THE PRODUCTION THEREOF.

United States Patent US. Cl. 260-515 A 11 Claims ABSTRACT OF THEDISCLOSURE Novel therapeutic compounds of the 'y,'y-diaryl-a,3-dihalocrotonic acid type specifically the dichloro and dibromocompounds and processes for the production thereof.

This invention relates to new 'y,'y-diaryl-a,;5-dihalogencrotonic acidshaving the general formula as indicated below (I).

Q X X CH t=t OOOH wherein X is a chlorine or bromine atom, R is afluorine or bromine atom, or a methyl, ethyl, or cycloalkyl radicalhaving 5 to 6 carbon atoms, and R is a hydrogen atom or methyl radical,and to a process for producing same, and to the use of such compounds astherapeutic agents.

The novel acids having the aforementioned general formula weresynthesized during an investigation of combinations having predeterminedantineoplastic effects, that is as a continuation of the previouslyreported research work by V. Ettel, M. Semonsky, V. Zikan, Chem. list46, 232, 1952, which work was concerned with the synthesis of theyy-diphenyl-a,,3-dichloroandyq-bis-(pchlorophenyl)-u,fl-dichlorocrotonic acid. Both acids were,however, in the indicated field, completely ineflective.

In accordance with the invention the production of the new acids iscarried out by reacting mucochloric or mucobromic acid with asubstituted benzene of the general formula (II) B1 wherein R and R havethe same meaning as in formula I, in a quantity of at least two molarequivalents, in the presence of anhydrous aluminum chloride, attemperatures in the range of 10 C. up to the boiling temperature of thereaction mixture.

The excess aromatic reactant, that is the substituted benzene of generalformula II, when used in a quantity greater than two mole equivalents,serves simultaneously as reaction medium and reactant and the excess canbe recovered to a great degree. In some cases, in particular when themucohalogen acid used is poorly dissolved in the aromatic reactioncomponents, it is advantageous, to use in lieu of a large excess ofthese compounds, an inert solvent medium which readily dissolves themucohalogen acid, for example, 1,2-dichlorethane. I

The condensation of the mucohalogen acid with the substituted benzene ofgeneral formula II in the presence of anhydrous aluminum chloride occurswith production of hydrogen chloride or hydrogen bromide andds o nly"moderately exothermic. After the reaction 'is' complete as indicated bycessation of the formation of hydrogen chloride or hydrogen bromide thereaction mixtureis decomposed by pouring it into an ice-hydrochloricacid mixture. After stirring the decomposed reaction mixture with awater immiscible low boiling solvent for example, chloroform, theorganic phase is separated. Low-boiling components are separated bydistillation and the re ain: der is permited tocrystallize. Theseparated 'product is dried under vaccum. By working up the motherliquor it is possible to obtain a=further fraction of the product. Theyield of 'yyy-diaryl-a,fl-dihalogencrotonic acids in most cases is aboutof the theoretical yield;

The wy-diaryl-a,fl-dihalogencrotonic acids of the'general formula I, inparticular those which are substituted-in the benzene nucleus with alkylradicals, have a significant antineoplastic, in other words,therapeutic, effect with experimental animals having a certain type ofexperimental tumor, and their toxicity is relatively low. It isespecially significant that the therapeutic effect of the aforementionedacids is also developed when they are administered orally.

Thus, for example, the -di-4-ethylphenyl-mB-dibromo-crotonic acid wastested on mice,'of the. race H, having transplanted Ehrlich-ascitestumor, said acid being administered beginning on the 3rd day after thetumor has been transplanted, in a daily dose of mg./kg. of weight for 12days (exceptv Saturday and Sunday). When thus used and as compared withalnon-treated control group, the test compound delays the tumor growth.by about 30% and increases the survival of the treated animals by 26%.Mice, of the race H, having a carcinoma of the type tumor Kr 2, whentreated with the aforementioned acid, in a daily dose of 50 mgJkg. ofweight and otherwise maintained under the same conditions, showed adelay or retardation of the tumor growthby'about 36%, and an increase inthe survival of the treated'animals by about 42%. The same type ofanimals having a tumor Sarkom S 37, when being treated with theaforementioned material, in a dose of 50 mgJ/kg. of weight per day, andotherwise maintaining the same experimental conditions, showed a delayor retardation in tumor growth of about 12% and produced an increase'of'survival of the treated animals by 28%. I

In comparison with these results there-was noted'completeineffectiveness with the 'y,'y-di-4-ethylphenyl-a,;8-dibromocrotonicacid with rats having a transplanted Yoshida-Ascitessarcoma in doses of50 to 100 mg./kg. per day by weight started on the second day after thetumor transplant, and otherwise with the same hereinbeforedescribedexperimental conditions. The acute toxicity (LD 50) determined with miceafter oral administration amounts to about 800 mg./kg.

There can not as yet be given a categorical and final explanationconcerning the mechanism of the antineoplastic effect of thewy-diaryl-a,fl-dihalogencrotonic acids of the general formula I as sucheifect is disclosed herein. What is notable, however, is thedetermination that the acids in vitro cause a retardation on the folicacid reductase otherwise called folatreductase and tetrahydro folic acidformylase. For example the 'y,'y-di-4-ethylphenyl-a,fl-dibromocrotonicacid causes, in a concentration of 25 ag/l. ml. in the incubationmedium, about a 73% retardation of the first, and in a concentration of,ug./l. ml. about a 50% retardation of the second enzyme.

EXAMPLE 1 'y,'y-di-4-methylphenyl-a,fl-dichlorocrotonic acid To amixture of g. toluene and 40 g. aluminum chloride there is added 33 g.of finely ground mucochorine Patented Aug; 13, '1 974 3 I acid underanhydrous'conditions and the mixture is stirred at aterpperatureof 20-25C. for 20 minutes. The stirring of the reaction mixture is continued atthe same temperature for one hour. The reaction mixture is allowed tostand for 24 hours after which it is poured into a mixture of 250 g. ofchopped ice and 75 ml. of concentrated hydrochlori c acid. Afteraddition of 200 ml. chloroform the mixture is shaken vigorously. Afterthe mixture has settled, the organic, phase is separated and dried withwater free sodium sulfate. The low boiling portions are distilled usingthe vacuum of a water jet pump. The residue is permittedtocrystallize.,The yield of the raw product amounts to 163g. Afterrecrystallization first in aqueous methanol and thereafter in diluteacetic acid there is obtained a pure product, mp. 178179.5 C.

I "EXAMPLE 2 'y,'y-di-4-ethylphenyl-oafl dibromocrotonic acid Into amixture of 40 g. ethyl benzene, and 8 g. aluminum chloride there isadded under the same conditions as set forth in Example 1, 10g. ofmucobromine acid. The reaction mixtnre is stirred for one hour. Afterworking up the "reaction mixture as set forth in Example 1, there isobtained 13.5 g. of a raw product which after recrystallization inchloroform is purified. mp. 137138 C.

EXAMPLE 3' 'y,-y-di-4-cyclohexylphenyl-a, 8-dichlorocrotonic acid Into amixture of 58 g. cyclohexylbenzene, 8.0 g. aluminum .chloride and 50ml." 1,2-dichlorethane there is added, under the same conditions as setforth in Example 1, 6.6 g. of 'rnucochlorine acid. The reaction mixtureis stirred for 2.5 hours at a temperature of 70 to 75 C. After work up"as inExample'l, with the only exception that dichlor oethanev is usedinstead of chloroform the raw prodnot in a yield of 88%. It is possibleby means of recrystallization with acetic acid to purify it. m.p.163-165 C.

In the same manner as the aforedescribed examples the followingcombinations were obtained:

r -di-4-ethylphenyl-a,,6-dichlorocrotonic acid, m.p.

133.5-135 C./ (aqueous acetic acid). 'y,'-di-3,4-dimethylphenyl-u,5-dichlorocrotonic acid, m.p.

168170 C./ (aqueous acetic acid). -di2,4-dimethylphenyhxfi-dichlorocrotonic acid, m.p.

. 174.5-176" (aqueous acetic acid).'y,'y-di-'2,S-dimethyI-phenyI-u,fi-dichlorocrotonic acid m.p.

F. 192-1935 C. (acetic acid). 'y,' -di-4-fluorphenyl-a,3-dichlorocrontonic acid, mp. 166-- 168 C. (acetic acid).

4 'wy-di-4-brominephenyl-a,fl-dichlorocrontonic acid, m.p.

182-1835 C. (acetic acid). -y,' -di-4-methylphenyl-a,fl-dibromocrotonicacid, m.p.

167-169 C. (aqueous acetic acid).-di-3,4-dimethylphenyl-a,B-dibromocrotonic acid, mp.

191-193 C. (acetic acid). 'y,'-di-2,4-dimethylpheny1-a,;3-dibromocrotonic acid, m.p.

206208 C. (aqueous acetic acid). -di-4-fluorphenyl-u,fl-dibromocrotonicacid, mp. 149- 151 C. (acetic acid).

What is claimed is: 1. w -diaryl-a,B-dihalocrotonic acid having thegeneral formula I wherein X is a chlorineor bromine atom, R is a bromineatom, a fluorine atom or a methyl, ethyl or cycloalkyl radical having 5to 6 carbon atoms, and R is a hydrogen atom or a methyl radical.

2. wy-bis-(4-ethylphenyl)-a,;3-dibromocrotonic acid. 3.'yq-bis-(4-methylpheny1)-a,,-I-dichlorocrotonic acid. 4. 'y,'y-biS-(4cyclohexylphenyl)-a, 8-dichlorocrotonic acid.

5. 'y,'y-bis-(4-ethylphenyl)-u,,8-dichlorocrotonic acid. 6.-(4,4-dimethylphenyl)-a,;8-dichlorocrotonic acid. 7. 'y,'y-biS-(2,4dimethylphenyl)-a,fi-dichlorocrotonic acid.

8. 'y,'y-biS-(2,5 dimethylphenyl)-a, 8-dichlorocrotonic acid.

9. ,'y-bis-(4-methylphenyl)-a,fi-dibromocrotonic acid. 1:10.'y,'y-biS-(3,4 dimethylphenyl)-a,;8-dibromocrotonic ac1 1d1.'y,'y-bis-(2,4 dimethylphenyl)-u,p-dibromocrotonic acl References CitedEttel et al.: Chem. Abstracts, vol. 47 (1952), p. 6903.

JAMES A. PA'ITEN, Primary Examiner US. Cl. X.R. 424-3 17

